Giardiasis is characterized by a clinical spectrum of acute to chronic symptoms ranging from diarrhea to malabsorption syndrome. One of the key questions in giardiasis is what are the pathogenic mechanisms that underly the disease? The host-parasite interface is the cornerstone of the disease state and, while many additional factors may contribute to the outcome, without the parasite there is no disease. Hence detailed knowledge of the molecular genetics of the parasite will help in unravelling the biological basis of its pathogenicity. G. lamblia displays a very high degree of genomic plasticity, i.e., it undergoes frequent chromosome rearrangements. These rearrangements may play a role in controlling gene expression and, thus, may affect the pathogenicity of the organism. The proposed studies investigate the basis of the rearrangements and the possible effects they have on gene expression. The specific aims of this proposal are: 1. To determine the mechanisms underlying chromosome rearrangements in G. lamblia. This will be done by determining the break points in a rearranged chromosome and identifying the participating DNA sequences and their chromosomal origin. 2. To identify genes encoded on rearranged chromosomes whose transcription is affected by the rearrangements. This will provide insight into the biological consequences of such recombination events and assist in determining the significance of the chromosome rearrangements in G. lamblia. 3. To compare the genomic organization of a series of clinical isolates of G. lamblia through the use of chromosome-specific probes and cloned genes as genetic markers. The chromosomal location of these markers will be established by karyotype analyses and fractionation of individual chromosomes. This will provide data on whether gene loci in G. lamblia are linked in the same chromosomes among different strains, and will outline conserved and diverged domains of the genome.